Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer-related deaths. See Parkin D. M., Lancet Oncology 2:533-43 (2001). The disease is often diagnosed late in the course of clinical manifestation. As a result, only 10-15% of patients are candidates for curative surgery. For the majority of HCC patients, systemic chemotherapies or supportive therapies are the mainstay treatment options. Nevertheless, most chemotherapeutic agents show limited effectiveness and have not been able to improve patient survival. See e.g., Yeo W. et al., J. of the National Cancer Institute 97:1532-8 (2005), Gish R. G. et al., J. of Clinical Oncology 25:3069-75 (2007), Ramanathan R. K. et al., J. of Clinical Oncology 24:4010 (2006), and O'Dwyer P. J. et al., J. of Clinical Oncology 24:4143 (2006). Recent Phase III randomized trial of Sorafenib, an oral multi-kinase inhibitor of the VEGF receptor, PDGF receptor, and Raf, on hepatitis B-related HCC patients showed for the first time to prolong survival of advanced stage patients. See Cheng A. L. et al., Lancet Oncology 10:25-34 (2009). However, the median overall survival only increased from 4.2 months in the placebo group to 6.5 months in the treatment group. Moreover, HCC is frequently chemotherapy-resistant and known to over-express multi-drug resistance genes, such as MDR1 (P-gp) and the multi-drug resistance proteins (MRPs). See e.g., Ng I. et al., American J. of Clinical Pathology 113:355-63 (2000), Endicott J. A. et al., Annual Review of Biochemistry 58:137-71 (1989), and Park J. G. et al., J. of the National Cancer Institute 86:700-5 (1994). The adverse clinical course of most HCC patients underscores much need for more efficacious chemotherapies and development of targeting strategies.
Taxanes (such as paclitaxel and docetaxel) are a class of diterpenoid drugs that have anti-tumor activity against a wide range of human cancers. Paclitaxel was originally isolated from the bark of the Yew tree, and was known to act by interfering with the normal function of microtubule breakdown. Paclitaxel binds to the β subunit of tubulin, the building blocks of microtubules, causing hyper-stabilization of the microtubule structures. The resulting paclitaxel/microtubule structure is unable to disassemble, thereby arresting mitosis and inhibiting angiogenesis. Although paclitaxel has been shown to be effective against various malignant tumor cells such as breast cancer, melanoma, and ovarian cancer, its effectiveness against HCC has been questioned. A phase II clinical trial of paclitaxel for HCC patients was reported in British Journal of Cancer, 78(1), 24-39, 1998, which concluded that paclitaxel had no significant anti-cancer effect in HCC patients. Docetaxel, on the other hand, was reported to be more active against HCC cells than paclitaxel. US Patent App. No. 2008/0045584.
Albumin-based nanoparticle compositions have been developed as a drug delivery system for delivering substantially water insoluble drugs such as taxanes. See, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; 6,749,868, and 6,537,579, 7,820,788 and also in U.S. Pat. Pub. No. 2007/0082838. The albumin-based nanoparticle technology utilizes the natural properties of the protein albumin to transport and deliver substantially water insoluble drugs to the site of disease. These nanoparticles are readily incorporated into the body's own transport processes and are able to exploit the tumors' attraction to albumin, enabling the delivery of higher concentrations of the active drug in the nanoparticles to the target site. In addition, the albumin-based nanoparticle technology offers the ability to improve a drug's solubility by avoiding the need for toxic chemicals, such as solvents, in the administration process, thus potentially improving safety through the elimination of solvent-related side effects.
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